Perioperative Esketamine Safety and Efficacy in Reducing Postoperative ENDometriosis PAIN (the ENDPAIN Trial): a Randomized Controlled Trial.

Endometriosis is a chronic condition affecting approximately 10% of women. It is frequently associated with persistent or recurrent pelvic and abdominal pain. The mechanisms underlying pain in endometriosis are complex and may include direct stimulation from endometriotic lesions and local inflammation, nerve involvement, and alterations in central pain processing. In some individuals, sensitization of the nervous system may result in pain persisting despite limited ongoing tissue injury.

Surgery is an important treatment option for patients whose symptoms are insufficiently controlled by medical therapy or in whom surgery is indicated to improve fertility. The primary aim of surgery is to remove endometriosis lesions, thereby reducing symptoms and improving quality of life.

However, patients undergoing surgery for endometriosis often experience more severe postoperative pain and require greater opioid consumption than patients undergoing other gynecological procedures. They may also be at increased risk of developing persistent postoperative pain, defined as pain that continues beyond the expected healing period and persists for months after surgery.

Esketamine is a well-established medication used in anesthesia and pain management. Its pharmacological effects and safety profile are well characterized. It is commonly administered in patients with pre-existing pain conditions or chronic opioid use. Previous studies suggest that esketamine may reduce acute postoperative pain, decrease opioid requirements, and provide benefits in certain neuropathic and chronic pain conditions. However, its efficacy and safety have not been systematically evaluated in patients undergoing surgery for endometriosis.

The ENDPAIN trial aims to evaluate the efficacy and safety of perioperative esketamine in patients undergoing surgery for endometriosis, with the goal of improving postoperative pain management and recovery.

Primary Objective: To evaluate the efficacy and safety of perioperative esketamine in reducing postoperative pain in patients undergoing intra-abdominal surgery for endometriosis.

Secondary Objectives: To collect information on preoperative and postoperative pain in patients undergoing surgery for endometriosis in order to improve understanding of the mechanisms and risk factors associated with severe acute postoperative pain and persistent postoperative pain.

To collect information on the effects of other analgesic medications used as part of routine clinical care in participating centres and to explore potential interactions between these medications and esketamine.

Primary Endpoint: Postoperative pain measured using a Numerical Rating Scale (NRS) at 30 minutes, and at 6, 12, 24, and 48 hours after surgery.

Secondary Endpoints:

Hospital-free days within 30 days after surgery, defined as the number of days spent alive and outside an acute-care hospital during the first 30 postoperative days.

Opioid consumption during the first 48 postoperative hours. Quality of Recovery (QoR-15) score. Serious adverse events. Adverse reactions associated with esketamine, including hypertension, tachycardia, hallucinations or dissociative symptoms, sedation, nausea, and vomiting.

Persistent postoperative pain and other patient-reported outcomes assessed three months after surgery.

Trial Design: The ENDPAIN trial is a triple-blinded, randomized, placebo-controlled clinical trial with a follow-up duration of three months.

Participants will be enrolled on the day of surgery. Most study data will be collected during the first 48 postoperative hours. A follow-up assessment will be conducted three months after surgery and may take place either during a study visit or by telephone, according to participant preference and local site procedures.

Trial Population: Adult patients undergoing elective surgery for endometriosis will be eligible for inclusion.

Patients will be excluded if they:

Do not provide informed consent. Have a known hypersensitivity or allergy to esketamine. Have a current or previous history of ketamine or esketamine misuse. Have a medical condition in which esketamine is contraindicated, such as elevated intracranial or intraocular pressure.

Have severe systemic disease (ASA Physical Status \> III). Have severe psychiatric illness. Intervention: Participants will be randomly assigned in a 1:1 ratio to one of two treatment groups. Participants allocated to the intervention group will receive esketamine 0.5 mg/kg following induction of anesthesia, followed by a continuous infusion of 0.15 mg/kg/hour until approximately 20 minutes before skin closure. Participants allocated to the control group will receive an equivalent volume of placebo consisting of sodium chloride solution (saline).